Therapeutic Potential of Curcumin in Major Retinal Pathologies

Therapeutic potential of curcumin in major retinal pathologies

Krishi V. Peddada, A’sha Brown, Vivek Verma & Marcella Nebbioso

International Ophthalmology The International Journal of Clinical Ophthalmology and Visual Sciences

ISSN 0165-5701

Int Ophthalmol DOI 10.1007/s10792-018-0845-y

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Int Ophthalmol https://doi.org/10.1007/s10792-018-0845-y

REVIEW

Therapeutic potential of curcumin in major retinal pathologies

Krishi V. Peddada . A’sha Brown . Vivek Verma . Marcella Nebbioso

Received: 1 September 2017 / Accepted: 29 January 2018 Ó Springer Science+Business Media B.V., part of Springer Nature 2018

Abstract that has been found to be efficacious in preventing and Purpose The retina is continually exposed to free treating a number of inflammatory diseases and radicals from its rich blood supply, numerous mito- neoplastic processes. Curcumin exerts anti-inflamma- chondria, and photons of light which strike its surface. tory, anti-tumor, antioxidant, and VEGF inhibition Most pathological processes that take place in the properties through modulation of numerous biochem- retina, such as inflammation, cell apoptosis, or angio- ical mediators. This makes curcumin particularly genesis, can hence involve free radicals directly or effective in retinal disorders. indirectly. Since inflammatory and oxidative stress Results Curcumin has found a role in slowing, and in pathways underlie retinal pathology, compounds that some cases even reversing, age-related macular degen- address these factors are therefore natural choices for eration, diabetic retinopathy, retinitis pigmentosa, pro- treatment. This review article summarizes and proliferative vitreoretinopathy, and retinal cancers. vides commentary on curcumin’s therapeutic potential Conclusions However, studies on curcumin’s effi- use in ophthalmology with principal focus on retinal cacy have been limited mostly to animal studies. dosorders. Moreover, the biomedical potential of curcumin is not Methods Curcumin (diferuloylmethane) is a com- easy to use, given its low solubility and oral bioavail- pound of the Indian spice turmeric (Curcuma longa) ability—more attention therefore has been given to nanoparticles and liposomes.

K. V. Peddada Keywords Anti-inﬂammatory drug Á Antioxidant Department of Ophthalmology, Drexel University, drug Á Anti-tumor drug Á Curcuma longa Á Curcumin Á Philadelphia, PA, USA Retinal diseases A. Brown Emory Eye Center, Emory University, Atlanta, GA, USA Introduction: structural aspects and details V. Verma of curcumin Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA The retina is continually exposed to free radicals from M. Nebbioso (&) its rich blood supply, numerous mitochondria, and Department of Sense Organs, Ocular Electrophysiology photons of light that strike its surface. The outer Center, Sapienza University of Rome, Viale del segment of the rods has a high content of polyunsat- Policlinico 155, 00161 Rome, Italy e-mail: [email protected] urated fatty acids that are particularly sensitive to 123 Author's personal copy

Int Ophthalmol peroxidation given their number of double bonds. The transcription factors, which in turn inhibit cellular inner segments of the rods are particularly rich in inflammatory responses and protect cells (Table 1). mitochondria, which contain activated oxygen species There has been a fair amount of work done that may cause damage if they leak out of cells. The assessing curcumin’s potential in ocular pathology. blood supply to the choroid is the richest in the retinal A review by Pescosolido et al. touches on many body, with vertebrate retinas having a sevenfold features that make curcumin a strong therapeutic agent higher rate of oxygen consumption per milligram of in many parts of the eye. Curcumin has found protein than other areas tested. Furthermore, the light application in dry eye syndrome by reducing the that hits the retina may trigger photooxidative pro- inflammation created by increased tear osmolarity. In cesses. Visible light in the blue wavelength forms the animal models of cataracts, curcumin was found to toxic compound A2E which targets cytochrome reduce the free radical damage and calcium influx that oxidase and induces irreversible DNA damage in is responsible for the proteolysis causing clouding of RPE cells. Most pathological processes that take place the lens. In diabetic retinopathy (DR), curcumin was in the retina, such as inflammation, cell apoptosis, or found to improve retinal microcirculation by inducing angiogenesis, can hence involve free radicals directly nitric oxide production. For age-related macular or indirectly [1–3]. degeneration (AMD), curcumin may provide therapy Because inflammatory and oxidative stress path- through beneficial effects on microglial cells that are ways underlie retinal pathology, compounds that responsible for drusen formation [4]. Researchers address these factors are therefore natural choices for have even hypothesized a possible therapeutic effect treatment. One such compound is curcumin (diferu- of the curcumin on protease inhibitors that help loylmethane), the orange and water-insoluble pigment maintain cellular and tissue homeostasis (Table 2) extracted from turmeric. It is derived from the rhizome [5, 6]. Some authors have even theorized a possible of Curcuma longa, a spice that belongs to the therapeutic effect of protease inhibitors in treatment of Zingiberaceae family. Chemically, curcumin incor- neovascularization and inflammation in animal mod- porates several functional groups. The aromatic ring els [5–7]. systems or phenols are connected by two a,b-unsat- In light of its angiogenesis-modulating profile and urated carbonyl groups. The diketones form anti-inflammatory properties, curcumin has great stable enols and are readily deprotonated to form potential in the treatment of inflammatory and neo- enolates; the a,b-unsaturated carbonyl group is a good vascular proliferative diseases of the retina. nucleophilic acceptor of a carbanion or another This article will summarize and provide commen- nucleophile [4]. tary on curcumin’s therapeutic potential with a focus The mechanism by which curcumin induces its on primary retinal disorders. effects is yet to be fully elucidated, but many studies have shown its relevance as a potent anti-inflammatory and immunomodulating agent. Curcumin is able Age-related macular degeneration to down-regulate the expression of genes involved in apoptosis, proliferation, and transformation, by AMD is the leading cause of worldwide blindness in inhibiting the nuclear factor jB (NF-jB) activation. the elderly and is projected to cost $59 billion Other studies demonstrated that curcumin may exert worldwide over the next 20 years [8]. It occurs when an anti-inflammatory effect through the activation of extracellular material, known as drusen or lipofuscin, peroxisome proliferator-activated receptor-c (PPAR- builds up between Bruch’s membrane and the retinal c), a group of transcriptional factors that regulate gene pigment epithelium (RPE). AMD may lead to geo- expression. In addition, curcumin inhibits the free graphic atrophy with loss of RPE and photoreceptors radicals production and so exhibits antioxidant prop- and may further progress to wet macular degeneration erties [4]. if new blood vessels bleed into the inner retinal layers. Indeed, curcumin with its pleiotropic activities can Evolving atrophic macular degeneration represents at modulate the expression and activation of many least 80% of all AMD and is currently without an cellular regulatory proteins such as chemokines, accepted treatment regimen [9, 10]. interleukins, hematopoietic growth factors, and 123 Author's personal copy

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Table 1 Curcumin inhibits or down-regulates a number of biochemical mediators 'Curcumin inhibits directly or indirectly G-proteins Lipo-oxygenase Cyclooxygenase Interleukin-1-6-8 (IL) Tumor necrosis factor-a (TNF-a) Free radicals production (antioxidant properties) Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) 'Curcumin down-regulates directly or indirectly Down-regulate the expression of IjBa gene Down-regulate the expression of prostaglandin E-2 (PGE-2) Down-regulate the expression of genes involved in apoptosis Down-regulate the expression of genes involved in cellular proliferation and transformation

Table 2 Molecules most commonly involved in maintaining cellular and tissue homeostasis Proteases and protease inhibitors mainly involved in retinal and uveal diseases

Iris and ciliary body SLPI: MMPs: Calpain inhibitor: Endophthalmitis, vitreous and retina disorders SLPI: MMPs: Calpain inhibitor: Angiogenesis, tumor, inflammation, oxidative stress (AMD), and fibrosis SERPINA3 K: TIMP- Calpain 3; inhibitor: Damage to: photoreceptors, RGCs (apoptosis), and ONFs. During: GL, MS, RD, RP, Caspase 3 MMPs: Calpain DR, PVR, etc. inhibitor: inhibitor: SLPI secretory leukocyte protease inhibitor, MMPs metalloproteinases, TIMP-3 MMP inhibitor-3, RGCs retinal ganglion cells, ONFs optic nerve fibers, GL glaucoma, MS multiple sclerosis, RD retinal detachment, RP retinitis pigmentosa, DR diabetic retinopathy, PVR proliferative vitreoretinopathy

AMD is primarily a heritable disease that occurs necrosis factor (TNF-a). AMD is also associated with when gene mutations predispose the retina to oxida- chronic diseases such as abdominal obesity [13], high tive stress and dysregulation of the complement cholesterol [14], cigarette smoking, and hypertension cascade [11]. In fact, research indicates that AMD [15] that can tip the body’s homeostasis into a pro- has a heritability of 71%, putting it on par with inflammatory milieu. Other stressors include Alzheimer’s and obesity [12]. There are two gene loci, increased light exposure that damages photoreceptors complement factor H (CFH) and ARMS2/HTRA1, [16]. These stresses can lead to free radical production implicated in the development of AMD. Complement and endothelial dysfunction in choroidal blood vessel factor H has a tyrosine to histidine change in AMD that walls as a part of a systemic vasculopathy [17]. leads to chronic complement activation and reduces its Vitamins such as AREDS, fatty acid supplementation ability to bind to oxidized lipids and clear apoptotic (DHA and EPA), as well as zinc additives, have cells [12]. The other gene locus, ARMS2, appears to proven helpful in dry AMD likely owing to their be involved in inflammation as well. Studies have ability to reduce oxidative stress. Current translational shown that knockout mice, or mice without the gene, and clinical studies are focused on enhanced photore- display lower expression of the pro-inflammatory ceptor neuroprotection, mechanisms to reduce local markers C3, C5, interleukin (IL)-6, IL-8, and tumor

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Int Ophthalmol oxidative stress, and even photoreceptor transplanta- end products with the release of superoxide radicals, tion [11]. which cross-link proteins and damage vascular and Curcumin decreases the transcription, translation, extravascular structures [26]. Hyperglycemia also and expression of the genes that increase inflammation induces oxidative stress pathways and promotes free in AMD. One study that modeled AMD through a radicals that contribute to the pathogenesis of DR [27]. pulsed H2O2 induction of retinal pigment cell aging These reactive species concentrate near retinal capil- showed that curcumin lead to decreased apoptosis and laries, leading to the loss of pericytes and to the thus higher cell viability. This study found that formation of micro-aneurysms, finally resulting in the curcumin reduced free radical expression as well as onset of vascular syndromes and DR. Therefore, an gene expression of the oxidative biomarkers superox- antioxidant treatment might be a valid strategy to limit ide dismutase (SOD), maleic dialdehyde, and glu- the initial damage and slow down or even prevent the tathione [18]. Another study showed that curcumin onset of DR. effects posttranscriptional regulation and silencing. Studies show that curcumin works through a variety Curcumin was found to up-regulate and down-regulate of mechanisms to limit the pathophysiological specific microRNAs (miRNAs) that regulate the changes to diabetic rat retina. One study showed that antioxidant system [19]. Curcumin also boosts curcumin prevented the degeneration of cellular enzymes that serve as cellular defense mechanisms organelles and increased the capillary basement in AMD, such as heme oxygenase-1 [20], and increase membrane thickness in the retina. Curcumin acted cytoprotective proteins such as nuclear-related factor by decreasing TNF-a, decreasing pro-angiogenic (Nrf2) [21]. These changes were consistent across vascular endothelial growth factor (VEGF), and different laboratory models of AMD. For example, in increasing the antioxidant enzymes SOD and catalase the light-induced retinal degeneration model of AMD, in this study [28]. Curcumin also plays a role in curcumin was found to inhibit nuclear factor- jB (NF- extracellular matrix production, which decreases as jB) and down-regulate cellular inflammatory genes cells undergo retinopathy. Curcumin increases levels [22]. Overall, laboratory studies have shown utility in of extracellular matrix production by increasing levels preventing cell death across different cellular models of mammalian excision repair cross-complementing of AMD. The mechanisms of action have been through (ERCC) 1 and ERCC4 enzymes [29]. In addition to its decreasing apoptotic rates of retinal pigment epithelial anti-apoptotic effects, curcumin also has anti-angio- (RPE) cells and decreasing overall inflammation. genic effects on the choroidal vasculature of rat Curcumin works on multiple processes involved in retinas. Diabetic microvasculature treated with cur- transcription and animal data on curcumin and trans- cumin had attenuated tortuosity, shrinkage, narrow- lation such as gene expression, nuclear translocation ing, and micro-aneurysms. Moreover, the choroidal of proteins, and silencing through miRNAs. microvasculature regenerated and repaired to near- normal characteristics [30]. Although studies did not compare curcumin against laser therapy or intravitreal Diabetic retinopathy injections, these studies did note that rats fed a diet with curcumin were found to have decreased VEGF in Diabetic retinopathy (DR) is the primary cause of their retinas [31]. blindness in patients from 25 to 74 years old in In summary, several animal studies have shown the industrialized countries [23]. This metabolic disorder benefits of curcumin on normalizing or preventing is a chronic inflammatory state that damages both the diabetic-induced changes in retina. These include photoreceptors and the blood vessels of the retina [24]. structural changes in capillaries, endothelial cellular Diabetes affects the vasculature by causing local organelles, and extracellular matrix production. Cur- hypertension and basement membrane thickening that cumin affects both the toxic neuronal damage and the disrupts the tight connections between the pericytes. vasculopathy that both underlie DR. The mechanisms This results in pericyte apoptosis and the release of of curcumin’s actions are indeed diverse and range cellular mediators that promote angiogenesis [25]. from hypoglycemic to anti-inflammatory to anti- Biochemically, a cascade of reactions result in the angiogenic. Human studies are needed to further formation and accumulation of advanced glycation investigate these relationships. 123 Author's personal copy

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Retinitis pigmentosa Curcumin’s antagonism to cellular mutation and eventual destruction, in addition to its decrease in Retinitis pigmentosa (RP) is a common inherited levels of cellular stress, gives it satisfactory function in retinal dystrophy that preferentially affects the rod other retinal dystrophies as well. Unfortunately, many photoreceptors, which control dim vision and periph- more studies need to be performed to confirm these eral vision. The disease process causes misfolding of findings before clinical studies on humans are rhodopsin proteins, which are G-protein-coupled underway. receptors involved in the visual transduction cascade. Conformational shift of proteins, dysregulation of molecular chaperones, and cellular cytotoxicity all Proliferative vitreoretinopathy disrupt protein folding and increase protein aggrega- tion. Current therapies are focusing on enhancing Curcumin can also reduce the incidence of prolifer- activities of chaperone proteins that augment folding ative vitreoretinopathy (PVR) after retinal detachment as well as other targets such as cell apoptosis, (RD) surgery. This condition is normally seen in mitochondrial dysfunction, and oxidative stress [32]. 8–10% of cases of rhegmatogenous RD and is caused Free radical formation, decline in retinal oxygenation, by vitreous fluid entering cell layers below the retinal and neurochemical changes complement genetic break. Vitreous cytokines such as TNF-a, transform- changes to play a role in degeneration of photorecep- ing growth factor-b2 (TGF-b2), platelet-derived tors. In addition, retinal blood flow may play a role in growth factor (PDGF), and interleukins release the pathogenesis, given the attenuation of retinal blood cytokines and ATP that promote retinal ischemia, cell vessels and atrophy of the choriocapillaris seen in RP proliferation, and tissue remodeling. The increased [33]. The specific biochemical pathways that lead to distance between retinal layers and choroidal blood cell death in RP are extremely diverse and include supply after detachment results in tissue hypoxia, genes involved in the phototransduction cascade, atrophy, and cell death. At the same time, RPE cells vitamin A metabolism, cytoskeletal proteins, cell stimulated by the cytokines lay down epiretinal signaling, intron splicing, intracellular trafficking, membranes which contract and may pull at the retina, and phagocytosis [34]. Retinal cell apoptosis is the predisposing to a second retinal detachment [38–40]. final common biochemical pathway seen in RP and is Several studies have cultured human RPE cells with caused by an alteration in the balance of pro- and anti- and without curcumin and used flow cytometry, apoptotic molecules [35]. transmission electron microscopy, and Western blot While the data regarding curcumin’s use in analysis to study features such as cell cycle progres- inherited retinal dystrophies such as RP are quite sion, apoptosis, and protein expression in PVR. Sun limited, the few studies that have been detailed are et al. [41] showed that curcumin added to human RPE promising. An animal study found that the number of cells inhibited proliferation in a dose-dependent and functional photoreceptors in the central retina after time-dependent fashion through cell cycle arrest at the curcumin injection was related to the amount of G0/G1 phase and induction of apoptosis. Gong et al. curcumin injected in a dose-dependent fashion [36]. [42] used human fetal RPE cells and found that Another study simulated RP in rats naturally through a curcumin was able to inhibit proliferation of those mutated P23H rhodopsin. Curcumin led to a number of cells through cell cycle arrest at the G2/M phase. benefits in these rat retinas—decreased formation of Curcumin, in this way, acts analogous to a tumor mutant protein aggregates, preservation of photore- suppressor gene by providing checkpoints to the ceptor morphology, increased levels of expression of pathological cell growth and division. Cell growth, photoreceptor marker genes, improvement in retinal in this case, is driven by growth factors that are a physiology on electroretinogram, facilitation of response to the stress and inflammation of RD surgery. translocation of mutant rhodopsin to the outer segment Alex et al. noted that curcumin promoted human RPE region, and decrease in the endoplasmic reticulum cell death through organized apoptotic pathways that stress in cells [37]. These studies are impactful included both caspase-3/7-dependent and caspase-8- because they show that curcumin has a measurable independent mechanisms. This contrasts with other impact on the cellular and biochemical levels. compounds that were likely to induce toxic necrotic 123 Author's personal copy

Int Ophthalmol pathways [43]. Lu et al. [44] identified several more thickness, and ultrasonographic hollowness. In uveal pathways through which apoptosis can occur, includ- melanoma, there is inhibition of apoptosis through ing the intrinsic pathway, caspase-3-dependent path- various intracellular signaling mechanisms such as ways, and caspase-3-independent pathways. These inactivation of the p53 pathway, defects in the Bcl-2 encouraging studies show that curcumin can also pathway, and activation of the pro-survival PI3K- effect changes on cells even after pathological changes AKT pathway; this one directly related to cellular have happened. It has multiple mechanisms to pro- quiescence, proliferation, cancer, and longevity [48]. mote self-destruction of those cells. One study Treatment for uveal melanoma chiefly depends on attributed the mechanism of apoptosis of RPE cells tumor size, with observation, radiotherapy, and enu- to increase in calcium and a decrease in mitochondrial cleation being the three primary treatment paradigms transmembrane potential [45]. [49, 50]. Curcumin has several promising effects on PVR, Many of the pro-apoptotic effects that have made including promoting cell cycle arrest at multiple curcumin extremely versatile in systemic cancers also checkpoints, increasing rates of apoptosis through make it useful in ocular malignancies. Mechanisms various pathways, and consistently inhibiting the such as promoting cell cycle checkpoints and apop- proliferation of RPE cells. Because currently all the tosis that led curcumin to be beneficial in PVR also studies have utilized in vitro cultures of human RPE lead it to be beneficial in cancers. However, this cells, the next step is assessing in vivo cultures. relationship is only theoretical at this point, as there Another major question will be how to get the are very few supportive studies available at this time. curcumin in optimal contact with the RPE, whether A study that assessed curcumin’s effects on the Y79 it be oral, intravenous, or intravitreal. retinoblastoma cell line found microarray expression pattern that showed that curcumin exerted its anti- cancer effect through modulation of miRNA expres- Retinal and choroidal tumors sion [51]. Another study assessed curcumin’s impact on cancerous cells by looking at its effect on a N18 cell While relatively rare in comparison to other neo- line, made up of retina ganglion cells hybrid with plasms, cancers that affect the eye are most likely to lymphoma cells. The study found that the mechanism manifest in the retina. Retinoblastoma is common in of inhibition of cancer cell growth was through DNA children and has an incidence of 1 in 15,000. damage and inhibition of DNA repair genes [52]. This Retinoblastoma has a strong genetic basis and occurs is particularly useful because it may act in conjunction when the tumor suppressor gene Rb1 is inactivated by with other mechanisms of cancer treatment, such as a familial mutation. If the second tumor suppressor radiation, which also damages DNA [53]. A second gene undergoes a sporadic mutation, cell cycle study also looked at curcumin’s effect on the N18 cell progression proceeds unchecked [46]. Next, ocular line and found that curcumin inhibited matrix metal- metastases have an incidence of approximately 20,000 loproteinases responsible for metastatic spread of per year, but rarely present to the ophthalmologist cancer cells [54]. Many more studies are needed to because patients’ visual symptoms are often less understand how curcumin may affect ocular cancers severe compared to their medical complaints at the such as retinoblastoma, uveal melanoma, and ocular given time. In addition, they tend to be a fairly low metastases. percentage relative to the incidence of primary cancers—one study showed that 2% of all lung cancers had ocular metastases [47]. A variety of Future work treatments have been used for these cancers, including radiotherapy, chemotherapy, photodynamic therapy, There are several strengths of curcumin as a thera- and intravitreal injections. Next, uveal melanomas are peutic compound. As a naturally occurring compound the most common primary cancers in adults. They start with pharmaceutical potential, curcumin has found as pigmented lesions in the eye that may be more itself in the food and drug category of ‘‘generally likely to exhibit malignant behavior if they have regarded as safe’’ [55]. Moreover, it is inexpensive, features such as associated fluid, increased tumor readily available, and natural. It can even be mixed in a 123 Author's personal copy

Int Ophthalmol patient’s normal diet, making it much easier to be cornea. The results show mild improvement in pen- regularly compliant. Consumption of curcumin has the etration, at a factor of 1.16 or 1.32 more if they are potential to have positive effects on multiple organ dispersed with the micelles at a ratio of either 1:1 or systems at once as well (Fig. 1). 3:1 [57, 58]. Another study showed that drugs given in However, it is primarily held back by its poor a lecithinized form showed improvements in retinal bioavailability. A very small fraction of the curcumin pathology, such as DR. There were improvements in that is consumed actually makes it into the blood diabetic microangiopathy as assessed by venoarterio- stream in its active state. Systemically, possible lar response, improved visual acuity, and improve- solutions have included structural modifications to ment in retinal flow [59]. Future research is looking the molecule and administering it with current ther- into on-demand release of drugs from liposomes, such apeutic treatments to look for synergistic effects. as an endogenous or exogenous stimulus controlling Novel delivery mechanisms including liposomes and the release of the drug [60]. In a 2010 patent, nanoparticles are currently being investigated as Chaniyilparampu proposed the use of cyclodextrins alternate mechanisms to deliver curcumin to the target to aid in the administration of curcumin as a topical sites [56]. To reach the retina, the particles could ophthalmic drop or eye gel formulation and tested this theoretically be delivered through the air–cornea to find that it was effective in reducing selenite- interface. However, because they need to have induced cataracts in rats [61]. hydrophilic properties in order to do so, studies have There is substantial work needing to be done in looked at micelles and their ability to penetrate the moving curcumin from the laboratory to the

Fig. 1 Chemical structure of curcumin. Curcumin inhibits the expression of nuclear growth factor jB (NF-jB). It also down- regulates tumor necrosis factor-a (TNF-a) and other pro-inﬂammatory and pro- ﬁbrotic molecules: phorbol ester (PMA), cyclooxygenase-2 gene (COX-2), subunit of NF-jB (IjBa), reactive oxygen species (ROS), prostaglandin E-2 (PGE-2), interleukins-1–6–8 (IL-1, IL-6, IL-8), osteopontin (OPN), and matrix metalloproteinase-9 (MMP- 9)

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Int Ophthalmol ophthalmology clinic. There are currently no human 9. Limoli PG, Vingolo EM, Morales MU, Nebbioso M, Limoli trials examining the ocular effects of curcumin. This is C (2014) Preliminary study on electrophysiological changes after cellular autograft in age-related macular degeneration. the next logical step, because curcumin has shown Medicine (Baltimore) 93(29):e355 potential in animal studies that have been done so far. 10. Limoli PG, Limoli C, Vingolo EM, Scalinci SZ, Nebbioso After this, there should be prospective studies com- M (2016) Cell surgery and growth factors in dry age-related paring traditional treatments such as AREDs vitamins macular degeneration: visual prognosis and morphological study. Oncotarget 7(30):46913–46923 to curcumin particles or oral curcumin. Another 11. 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